Small molecule inhibitors targeted at Bcl-2

Abstract

A method for promotion of cell death in tumor cells using tricylo-dibenzo-diazocine-dioxides that bind to a pocket of Bcl-2 and block the Bcl-2 anti-apoptotic function. A method of use of a compound of the general structural Formula (I) for use in treatment of cancer: wherein X and Y, and R and R 1 , and R 2 , R 3 , R 4 and R 5 , and A and A 1 , have any of the values defined in the specification.

What is claimed is:  
     
       1. A method for promoting apoptosis in cells overexpressing Bcl-2 in a subject comprising administering to said subject a therapeutically effective amount of a compound of the general formila:                    
       wherein X and Y are each independently hydrogen, OR or OR 1 ; wherein R and R 1  are each independently hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 3 -C 8 ) cycloalkyl, phenyl or trifluoromethyl; wherein R 2 , R 3 , R 4  and R 5  are each independently hydrogen, hydroxy, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 3 -C 8 ) cycloalkyl, phenyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, amino, (C 1 -C 6 ) monoalkylamino, or (C 1 -C 6 ) dialkylainino; A and Al are each independently 1 to 3 substituents selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, fluorine, chlorine, bromine, iodine, (C 1 -C 6 ) alkyl-alkoxy, amino, (C 1 -C 6 ) alkylarnino and (C 1 -C 6 ) dialkylamino; and pharmaceutically acceptable salts thereof.  
     
     
       2. The method of  claim 1 , wherein the compound is administered to a mammal. 
     
     
       3. The method of  claim 2 , wherein the mammal is a human. 
     
     
       4. The method of  claim 1 , wherein the compound is                    
       (2,9-dimetboxy-11,12-dihydrodibenzo-[c,g][1,2] diazocine-5,6-dioxide), and pharmaceutically acceptable salts thereof.  
     
     
       5. The method of  claim 4  wherein the compound is administered to a mammal. 
     
     
       6. The method of  claim 5  wherein the mammal is a human. 
     
     
       7. A pharmaceutical composition comprising a compound of the general formula:                    
       wherein X and Y are each independently hydrogen; OR or OR 1 ; wherein R and R 1  are each independently hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 3 -C 8 ) cycloalkyl, phenyl or trifluoromethyl; wherein R 2 , R 3 , R 4  and RS are each independently hydrogen, hydroxy, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 4 -C 8 ) cycloalkyl, phenyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, amino, (C 1 -C 6 ) monoalkylamino, or (C 1 -C 6 ) dialkylamino; A and Al are each independently 1 to 3 substituents selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, fluorine, chlorine, bromine, iodine, (C 1 -C 6 ) alkyl-alkoxy, amino, (C 1 -C 6 ) alkylamino and (C 1 -C 6 ) dialkylaznino; and a pharmaceutically acceptable carrier.  
     
     
       8. A pharmaceutical composition comprising a compound of the general formula:                    
       and a pharmaceutically acceptable carrier.